1. Field of Invention
This invention relates to a novel process for making antibacterial cephalosporins from allenylazetidinone derivatives.
More specifically, as shown in Scheme (A), the process involves converting 2-(3-amino-2-oxo-azetidin-1-yl)-2,3-butadienoate [allenylazetidinone] of formula I to a cephalosporin of formula II using an organo-copper reagent. ##STR2## In Scheme (A), R.sup.1, R.sup.2, R.sup.3, R.sup.4, and n are defined hereinbelow.
2. Description of Related Art
Farina et al , in Tetrahedron Letters, 29, No. 47, p. 6043 (1988), disclose reactions of C-3 trifloxy cephalosporins of formula III with organo-stannanes in the presence of a palladium (0) catalyst to transfer a variety of R.sup.5 radicals. Examples of R.sup.5 radicals include alkenyl, alkynyl and aryl. ##STR3##
Similarly, Kant et al., in Tetrahedron Letters, 31, No. 24, p. 3389 (1990), disclose a process (Scheme C) whereby a compound of formula V is reacted with an organo-copper reagent LiCu(R.sup.6) or Li.sub.2 Cu(CN)(R.sup.6).sub.2 to afford a compound of formula VI. ##STR4## in Scheme (C), R.sup.6 is alkyl, phenyl, or alkenyl; R.sup.7 is NHCOCH.sub.2 OPh or NHCOCH.sub.2 Ph; R.sup.8 is SO.sub.2 CF.sub.3, SO.sub.2 C.sub.6 H.sub.4 -p-NO.sub.2, or SO.sub.2 C.sub.6 H.sub.4 -p-CH.sub.3 ; and R.sup.9 is CHPh.sub.2 or CH.sub.2 C.sub.6 H.sub.4 -p-OCH.sub.3.
Conway et al., in the Canadian Journal of Chemistry, 56, p 1335 (1978), disclose the allenylazetidinone derivative of formula VII. ##STR5## Due to the direct attachment of a methylene group to the C-4 position of the azetidinone ring, the compound of formula VII cannot be directly converted to a cephem structure.
U.S. Pat. No. 4,550,162, issued to Woodward et al on Oct. 29, 1985, discloses cephalosporins of formula VIII in which R.sup.13 is an acyl group; R.sup.11 represents an optionally substituted aromatic heterocyclic radical with up to 15, preferably up to 9, carbon atoms and at least one ring nitrogen atom and optionally a further ring hetero-atom, such as oxygen or sulfur, which radical is bonded to the thio group --S-- by one of its ring carbon atoms, which is bonded to a ring nitrogen atom by a double bond, or R.sup.11 is --SO.sub.2 Q' in which Q' is an optionally substituted aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon with up to 18, preferably up to 10, carbon atoms; and R.sup.10 has the meaning of --SO.sub.2 Q' as defined above. ##STR6## The above compounds of formula VIII has never been converted to allenylazetidinones of the instant invention, but was transformed to the enamines of formula IX, in which R.sup.11, R.sup.12 and R.sup.13 have the same meaning as above and NR.sup.15 R.sup.16 is dialkylamino.
There has been several reports of reactions of allenylazetidinones with organo-copper reagents. Notably, for example, Fleming et al., in Tetrahedron, 45, No. 2, p. 413 (1989) disclose silyl cupration of the unsubstituted allene of formula X followed by direct treatment of the intermediate with an electrophile E.sup.+, such as proton, carbon electrophile, or halogen to afford a compound of formula XI' or XI''. ##STR7##
Other more remotely related examples of the reactions of organo-copper reagents with functionalized allenes can be found in: Corey et al., Tetrahedron Letters, 24, No. 32, p. 3291 (1983); Ohmori et al., Tetrahedron Letters, 23, No. 45, p. 4709 (1982); and Clinet et al., Nouveal Journal de Chemie, 1, p. 373 (1977).